CN111269132A - Method for preparing chiral β -trifluoromethyl- β -hydroxy- α -amino acid and derivative thereof - Google Patents

Method for preparing chiral β -trifluoromethyl- β -hydroxy- α -amino acid and derivative thereof Download PDF

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CN111269132A
CN111269132A CN202010071330.5A CN202010071330A CN111269132A CN 111269132 A CN111269132 A CN 111269132A CN 202010071330 A CN202010071330 A CN 202010071330A CN 111269132 A CN111269132 A CN 111269132A
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trifluoromethyl
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CN111269132B (en
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赵宝国
章亮亮
赵国庆
程奥林
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Abstract

The invention relates to a method for preparing chiral β -trifluoromethyl- β -hydroxy- α -amino acid and derivatives thereof, which comprises the steps of weighing tert-butyl glycinate and derivatives thereof, trifluoromethyl ketone, acid and a chiral N-methyl pyridoxal catalyst, adding a solvent, and reacting to obtain a target product chiral β -trifluoromethyl- β -hydroxy- α -amino acid and derivatives thereof.

Description

Method for preparing chiral β -trifluoromethyl- β -hydroxy- α -amino acid and derivative thereof
Technical Field
The invention belongs to the technical field of compound preparation, and relates to a method for preparing chiral β -trifluoromethyl- β -hydroxy- α -amino acid and derivatives thereof.
Background
In organisms, compounds containing free amino groups can directly participate in the reaction, for example, glycine can react with electrophilic reagent aldehyde to generate β -hydroxy α -amino acid under the catalysis of enzyme, the reaction condition is mild, and glycine directly participates in the reaction without any protection6Which are mainly present in the form of phosphate derivatives in vivo (PMP and PLP), are water-soluble vitamins whose main role is to participate as coenzyme factors in various enzyme-catalyzed reactions. Chemists have found that pyridoxal can also induce the addition of glycine to an aldehyde in the absence of an enzyme. The Kuzuhara and Breslow problem groups have made much pioneering work in the addition of glycine to aldehyde with chiral pyridoxal participation [ h.kuzuhara, n.watanabe, m.ando, j.chem.soc., chem.commu.1987, 95-96; m.ando, h.kuzuhara, ball.chem.soc.jpn.1990, 63, 1925-1928; J.T.Koh, L.Delaude, R.Breslow, J.am.chem.Soc.1994,116,11234-11240]Then, Richard discovered that pyridoxal can react with glycine in water to form the corresponding aldol addition product [ K.Toth, T.L.Amyes, J.P.Richard, J.P.G.Malthose, M.E.N I Beilli, J.Am.Chem.Soc.2004,126, 10538-10539; K.Toth, L.M.Gaskell, J.P.Richard, J.Org.Chem.2006,71, 7094-]。
In the field of medicinal chemistry, trifluoromethyl is an important chemical group, and has high lipid solubility, good metabolic stability, high electronegativity and bioavailability, so that the trifluoromethyl has wide application in bioactive molecules [ Tomashenko, O.A.; Grushin, V.V.Chem.Rev.2011,111,4475-4521 ]. in some medicinal examples, trifluoromethyl can replace methyl or chlorine atoms, and trifluoromethyl medicaments have been the focus of attention since the last 20 years.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a method for preparing chiral β -trifluoromethyl- β -hydroxy- α -amino acid and derivatives thereof, mainly provides pyridoxal catalytic glycine and derivatives thereof for innovation, and also provides a novel method for preparing the chiral β -trifluoromethyl- β -hydroxy- α -amino acid and the derivatives thereof by utilizing the asymmetric aldol reaction of the pyridoxal catalytic glycine and the derivatives thereof with trifluoromethyl ketone.
The purpose of the invention can be realized by the following technical scheme:
one of the technical schemes of the invention provides a novel biaryl structure chiral N-methyl pyridoxal catalyst, which has the following structural general formula:
Figure BDA0002377367840000021
wherein the content of the first and second substances,
R1is hydrogen or C1-C24Hydrocarbyl radical, R2And R3Each independently is hydrogen or C1-C24A hydrocarbyl group.
Further, R1Selected C1-C24The hydrocarbyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, (1-phenyl) ethyl, 1-naphthyl, 2-naphthyl or halogen.
Further, R2Or R3Selected C1-C24The hydrocarbon group is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2, 6-biphenyl, 3, 5-biphenyl, 1-naphthyl or 2-naphthyl.
C of the invention1-C24C in (1)1Refers to a group having 1 carbon atom, C24Means a group having 24 carbon atoms, C1-C24Then refers to a group having 1-24 carbon atoms, the remainder being C8The same meaning is also analogized.
Further, the catalyst is a compound with (R, S), (S, S), (S, R) or (R, R) configuration, and the structure of the catalyst is as follows:
Figure BDA0002377367840000031
the second technical scheme of the invention provides a preparation method of a novel biaryl structure chiral N-methyl pyridoxal catalyst, which comprises the following steps:
1) resolving carboxylic acid compound 5' by adopting (S) -BINOL to obtain compound 6 with two configurations;
2) taking a compound 6 with a single configuration, removing BINOL under the action of alkali, and then acidifying to obtain a chiral acid compound 5 with a single configuration;
3) condensing a chiral acid compound 5 with a single configuration with a chiral amino alcohol compound 7 to generate a compound 8;
4) the compound 8 is firstly methylated and then hydrolyzed under the action of acid to obtain the target product pyridoxal catalyst.
More specifically, the method comprises the following steps:
(1) placing carboxylic acid compounds 5', (S) -BINOL, a condensing agent and alkali in a solvent for reaction to obtain a compound 6 with two configurations;
(2) taking a compound 6 with a single configuration, removing BINOL under the action of alkali, and then acidifying to obtain a chiral acid compound 5 with a single configuration;
(3) condensing a chiral acid compound 5 with a single configuration with a chiral amino alcohol compound 7 to generate a compound 8;
(4) firstly, obtaining a methylated intermediate from the compound 8 under the action of methyl iodide, and hydrolyzing the methylated intermediate under the action of acid to obtain a target product pyridoxal catalyst;
the structural general formulas of the carboxylic acid compound 5', the compound 6 with two configurations, the chiral acid compound 5 with two configurations, the chiral amino alcohol compound 7 and the compound 8 are respectively as follows:
Figure BDA0002377367840000041
the above process can be represented by the following flow:
Figure BDA0002377367840000051
further, in the step (1), the molar ratio of the carboxylic acid compound 5' to the condensing agent is 1: (1-5);
in the step (2), the molar ratio of the compound 6 to the base is 1: (1-10);
in the step (3), the molar ratio of the chiral acid compound 5 to the chiral amino alcohol compound 7 is 1: (1-5);
in the step (4), the molar ratio of the compound 8 to the methyl iodide is 1: (1-50).
Further, in the step (1), the reaction temperature is-20-50 ℃, and the reaction time is 1-48 h;
in the step (2), the reaction temperature is-20-120 ℃, and the reaction time is 1-72 h;
in the step (3), the reaction temperature is 0-100 ℃, and the reaction time is 1-24 h;
in the step (4), the reaction temperature is 0-100 ℃, and the reaction time is 1-48 h.
Further, the base used is one or a combination of more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, calcium hydride, potassium fluoride, triethylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, N-dimethylaniline, N-diethylaniline, 1, 4-diazabicyclooctane, diazabicyclododecane, N-butyllithium, 1, 4-dimethylpiperazine, 1-methylpiperidine, 1-methylpyrrole, quinoline, or pyridine.
Further, the acid used is one or a combination of sulfuric acid, hydrochloric acid, a dichloromethane solution of hydrochloric acid, a methanol solution of hydrochloric acid, a tetrahydrofuran solution of hydrochloric acid, a dioxane solution of hydrochloric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid.
Further, the solvent used is water, benzene, toluene, xylene, trimethylbenzene, acetonitrile, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, chloroform, dichloromethane, methanol, ethanol, isopropanol, tert-butanol, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide or N-methylpyrrolidinone.
The third technical scheme of the invention provides an application of a novel biaryl structure chiral N-methyl pyridoxal catalyst, which is used for preparing chiral β -trifluoromethyl- β -hydroxy- α -amino acid and derivatives thereof, namely, the chiral pyridoxal is used for catalyzing asymmetric aldol reaction of glycine and derivatives thereof and trifluoromethyl ketone, namely, the chiral pyridoxal catalyst is used for synthesizing chiral β -trifluoromethyl- β -hydroxy- α -amino acid and derivatives thereof, and the specific process comprises the following steps:
weighing tert-butyl glycinate and derivatives thereof, trifluoromethyl ketone, acid and chiral N-methyl pyridoxal catalyst, adding a solvent, and reacting to generate corresponding chiral β -trifluoromethyl- β -hydroxy- α -amino acid and derivatives thereof;
the structural formulas of the tert-butyl glycinate or the derivative thereof, the trifluoromethyl ketone, the chiral β -trifluoromethyl- β -hydroxy- α -amino acid or the derivative thereof are respectively as follows:
Figure BDA0002377367840000061
wherein R is4、R5Each independently is hydrogen, or any of the following substituted or unsubstituted groups: c1～C24A hydrocarbon group of3～C30Cycloalkyl or aryl of, C1～C24Carbonyl group of (C)1～C24Sulfonyl or phosphoryl groups.
The catalytic reaction process is specifically as follows:
Figure BDA0002377367840000071
further, R5When it is a substituted group, it means substituted with any of the following substituents: halogen, C1～C8A hydrocarbon group of3～C12Cycloalkyl or aryl of, C1～C8Carbonyl group of (C)1～C8Sulfonyl or phosphoryl, C1～C8Alkoxy or amine groups of (a). More preferably, the carbonyl group means an aldehyde group, a ketocarbonyl group, an ester carbonyl group, a carboxyl group, an amide group or the like.
Further, the acid used is sulfuric acid, hydrochloric acid, a dichloromethane solution of hydrochloric acid, a methanol solution of hydrochloric acid, a tetrahydrofuran solution of hydrochloric acid, a dioxane solution of hydrochloric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid.
Further, the solvent used is one or more of the following solvents:
water, benzene, toluene, xylene, trimethylbenzene, acetonitrile, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, carbon tetrachloride, chloroform, dichloromethane, 1, 2-dichloroethane, methanol, ethanol, isopropanol, N-propanol, N-butanol, tert-butanol, trifluoroethanol, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.
Further, the molar ratio of the tert-butyl glycinate or the derivative thereof to the trifluoromethyl ketone is 0.5: 1-5: 1;
the molar ratio of chiral N-methyl pyridoxal catalyst to trifluoromethyl ketone was 0.0001: 1-0.5: 1;
the reaction temperature is-40 to 100 ℃, and the reaction time is 1 to 144 hours.
It is to be noted that the numbers in compound 5, compound 6 and the like used in the present invention are names combined with "compound" to distinguish them respectively.
Compared with the prior art, the invention has the following advantages:
(1) pyridoxal is a very important compound with good biological activity, in a biological system, the pyridoxal is a coenzyme of a plurality of biological enzymes, can catalyze glycine derivatives to carry out addition reaction on aldehydes or ketones to synthesize chiral β -hydroxy- α -amino acid derivatives, the invention designs and synthesizes a chiral pyridoxal catalyst, and the small molecular compound can be used for carrying out a bionic aldol reaction process to realize the rapid and effective synthesis of the chiral β -trifluoromethyl- β -hydroxy- α -amino acid derivatives.
(2) The chiral pyridoxal catalyst developed in the invention can be prepared by multi-step reaction of cheap and easily available raw materials, has mild reaction conditions, is easy to amplify mostly and can be prepared on a large scale.
(3) The bionic aldol reaction catalyzed by a pyridoxal catalyst is a novel method for preparing a chiral β -trifluoromethyl- β -hydroxy- α -amino acid derivative, and the method simulates the generation process of β -hydroxy- α -amino acid in an organism, namely the chiral pyridoxal catalyst is condensed with tert-butyl glycinate to form aldimine, α C-H of the aldimine is deprotonated to obtain an active carbanion intermediate, and then trifluoromethyl ketone is added and hydrolyzed to generate an β -trifluoromethyl- β -hydroxy- α -amino acid derivative, and the chiral pyridoxal catalyst is regenerated to complete the catalytic cycle process.
(4) The pyridoxal catalyst disclosed by the invention catalyzes the reaction without protecting and deprotecting amino groups, has the advantages of very mild reaction conditions, low sensitivity to water and air, stable reaction, easiness in operation, high enantioselectivity and better yield, and is an effective method for preparing the chiral β -trifluoromethyl- β -hydroxy- α -amino acid derivative.
Detailed Description
The present invention will be described in detail with reference to specific examples. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.
In the following examples, the chiral pyridoxal catalyst used was prepared by the following preparative scheme:
Figure BDA0002377367840000091
the above chiral pyridineIn the preparation of the pyridoxal catalyst, R is determined according to the requirements of the prepared target product1、 R2、R3Can be adjusted arbitrarily within the following range:
R1can be hydrogen or C1-C24A hydrocarbon group of R2And R3Each independently is hydrogen or C1-C24A hydrocarbon group of (a); r1Selected C1-C24The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, (1-phenyl) ethyl, 1-naphthyl, 2-naphthyl, halogen or the like; r2Or R3Selected C1-C24The hydrocarbon group is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2, 6-biphenyl, 3, 5-biphenyl, 1-naphthyl, 2-naphthyl or the like.
In addition, the kind and amount of each corresponding reagent can be adjusted within the following range (i.e., any middle point or end point is selected) as required:
the molar ratio of the carboxylic acid compound 5' to the condensing agent is 1: (1-5); in the step (2), the molar ratio of the compound 6 to the base is 1: (1-10); in the step (3), the molar ratio of the chiral acid compound 5 to the chiral amino alcohol compound 7 is 1: (1-5); in the step (4), the molar ratio of the compound 8 to the methyl iodide is 1: (1-50).
In the step (1), the reaction temperature is-20-50 ℃, and the reaction time is 1-48 h; in the step (2), the reaction temperature is-20-120 ℃, and the reaction time is 1-72 h; in the step (3), the reaction temperature is 0-100 ℃, and the reaction time is 1-24 h; in the step (4), the reaction temperature is 0-100 ℃, and the reaction time is 1-48 h.
The base used in each step is one or a combination of more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, calcium hydride, potassium fluoride, triethylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, N-dimethylaniline, N-diethylaniline, 1, 4-Diazabicyclooctane (DABCO), Diazabicyclododecane (DBU), N-butyllithium, 1, 4-dimethylpiperazine, 1-methylpiperidine, 1-methylpyrrole, quinoline, or pyridine; the acid is one or more of sulfuric acid, hydrochloric acid, dichloromethane solution of hydrochloric acid, methanol solution of hydrochloric acid, tetrahydrofuran solution of hydrochloric acid, dioxane solution of hydrochloric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid; the solvent is water, benzene, toluene, xylene, trimethylbenzene, acetonitrile, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, chloroform, dichloromethane, methanol, ethanol, isopropanol, tert-butanol, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide or N-methylpyrrolidone.
In addition, the rest of the raw material reagents or processing techniques, if not specifically mentioned, are all conventional and commercially available raw materials or conventional processing techniques in this field.
Example 1:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4a
Figure BDA0002377367840000101
Trifluoromethyl ketone 3a (0.252g,1.0mmol), tert-butyl glycinate 2(0.195g,1.50mmol), CH were successively reacted3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, injection of CH2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol), stirring at room temperature for 1 hour, removing the organic solvent by rotation, and column-chromatographing to give the compounds anti-4a (pale yellow solid) and syn-4a (pale yellow solid), (total weight of product 0.324g, total yield 85%).
Dr value of 4a is determined by1H NMR analysis shows that the reaction crude product is obtained, and the dr value of the reaction crude product is 1: 5; anti-4aThe ee value of (a) is 86% by analyzing the N, N-thiocarbonyldiimidazole derivative by HPLC; the ee value of syn-4a was 96% by HPLC analysis of the N, N-thiocarbonyldiimidazole derivative.
anti-4a:Light yellow solid；1H NMR(400MHz,CDCl3)δ8.13(dd,J＝8.4,1.2Hz,1H),7.85(dd,J＝8.0,1.6Hz,1H),7.72(dt,J＝8.0,1.0Hz,1H),7.50-7.43(m,J＝ 19.2,8.0,6.8,1.4Hz,2H),7.42-7.32(m,2H),3.76(s,1H),3.40-3.20(m,2H),2.17- 2.01(m,2H),1.48(s,9H).13C NMR(100MHz,CDCl3)δ171.9,138.0,134.1,131.9, 128.9,127.0,126.20(JC-F＝285Hz),126.17,126.1,125.73,125.65,123.9,83.9,75.7 (JC-F＝26Hz),57.0,53.6,33.7,27.9,26.1.HRMS m/z Calcd.for C20H25F3NO3(M+H)+: 384.1781；Found:384.1782.
syn-4a:Light yellow solid；1H NMR(400MHz,CDCl3)δ8.17(d,J＝8.0Hz,1H),7.87(dd,J＝8.0,1.6Hz,1H),7.75(dd,J＝8.0,1.6Hz,1H),7.57-7.48(m,2H),7.45- 7.35(m,2H),3.68(s,1H),3.50-3.30(m,1H),3.25-3.13(m,1H),2.43-2.27(m,2H), 1.52(s,9H).13C NMR(100MHz,CDCl3)δ170.3,137.8,134.0,131.8,128.8,127.0, 126.2,126.14(JC-F＝287Hz),126.11,125.6,123.9,83.3,74.6(JC-F＝26Hz),56.6,32.9, 28.0,26.1.HRMS m/z Calcd.for C20H25F3NO3(M+H)+:384.1781；Found:384.1782.
Example 2:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4b
Figure BDA0002377367840000111
Trifluoromethyl ketone 3b (0.278g,1.0mmol), tert-butyl glycinate 2(0.195g,1.50mmol), CH were successively reacted3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three timesInjection of CH2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol), stirring at room temperature for 1 hour, removing the organic solvent by spinning, and performing column chromatography to obtain the compounds anti-4b (pale yellow solid) and syn-4b (pale yellow solid), (total weight of product 0.372g, total yield 91%).
Dr value of 4b is determined by1H NMR analysis is carried out on the reaction crude product, and the dr value of the reaction crude product is 1: 6; the ee value of anti-4b is obtained by analyzing the derivative of N, N-thiocarbonyldiimidazole through HPLC, and the ee value is 87%; the ee value of syn-4b was 97% as determined by HPLC analysis of a derivative of N, N-thiocarbonyldiimidazole.
anti-4b:Light yellow solid；1H NMR(400MHz,CDCl3)δ7.60-7.55(m,2H), 7.54-7.49(m,2H),7.45-7.37(m,2H),7.36-7.21(m,3H),3.69(s,1H),2.90-2.80 (m,2H),2.07-1.94(m,2H),1.50(s,9H).13C NMR(100MHz,CDCl3)δ171.8,141.2, 140.9,139.2,128.90,128.85,127.4,127.20,127.1,126.2(JC-F＝285Hz),83.8,75.5(JC-F＝26Hz),56.8,34.3,28.5,28.0.HRMS m/z Calcd.for C22H27F3NO3(M+H)+:410.1938； Found:410.1940.
syn-4b:Light yellow solid；1H NMR(400MHz,CDCl3)δ7.64-7.51(m,4H), 7.48-7.40(m,2H),7.38-7.28(m,3H),3.60(s,1H),3.03-2.69(m,2H),2.35-2.20 (m,2H),1.53(s,9H).13C NMR(100MHz,CDCl3)δ170.3,141.0,140.7,139.2,129.0, 128.8,127.3,127.2,127.1,126.2(JC-F＝286Hz),83.2,74.4(JC-F＝26Hz),56.5,33.6, 28.6,28.0.HRMS m/zCalcd.for C22H27F3NO3(M+H)+:410.1938；Found:410.1939.
Example 3:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4c
Figure BDA0002377367840000121
Trifluoromethyl ketone 3c (0.216g,1.0mmol), tert-butyl glycinate 2(0.195g,1.50mmol) were successively introduced,
CH3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, injection of CH2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol), stirring at room temperature for 1 hour, removing the organic solvent by spinning, and performing column chromatography to obtain the compounds anti-4c (pale yellow solid) and syn-4c (pale yellow solid), (total weight of product 0.292g, total yield 84%).
Dr value of 4c is determined by1H NMR analysis shows that the reaction crude product is obtained, and the dr value of the reaction crude product is 1: 5; the ee value of anti-4c is obtained by analyzing the derivative of N, N-thiocarbonyldiimidazole through HPLC, and the ee value is 86 percent; the ee value of syn-4c was 93% as determined by HPLC analysis of a derivative of N, N-thiocarbonyldiimidazole.
anti-4c:Light yellow solid；1H NMR(400MHz,CDCl3)δ7.10(s,4H),3.68(s,1H),2.85-2.70(m,2H),2.32(s,3H),2.02-1.94(m,2H),1.49(s,9H).13C NMR(100 MHz,CDCl3)δ171.8,138.7,135.6,129.3,128.3,126.2(JC-F＝286Hz),83.8,75.5(JC-F＝ 26Hz),56.8,34.4,28.4,28.0,21.1.HRMS m/z Calcd.for C17H25F3NO3(M+H)+: 348.1781；Found:348.1783.
syn-4c:Light yellow solid；1H NMR(400MHz,CDCl3)δ7.21-6.97(m,4H),3.58(s,1H),3.02-2.65(m,2H),2.33(s,3H),2.24-2.15(m,2H),1.52(s,9H).13C NMR (100MHz,CDCl3)δ170.3,138.5,135.6,129.3,128.4,126.2(JC-F＝286Hz),83.1,74.4 (JC-F＝26Hz),56.4,33.7,28.4,27.8,21.0.HRMS m/z Calcd.for C17H25F3NO3(M+H)+: 348.1781；Found:348.1783.
Example 4:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4d
Figure BDA0002377367840000131
Trifluoromethyl ketone 3d (0.278g,1.0mmol), glycine tert-butyl ester 2(0.195g,1.50mmol), CH3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, CH injection2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol) at room temperature for 1 hour, removing the organic solvent by spinning, and performing column chromatography to obtain the compounds anti-4d (pale yellow solid) and syn-4d (pale yellow solid), (total weight of the product 0.271g, total yield 66%).
Dr value of 4d is determined by1H NMR analysis shows that the reaction crude product is obtained, and the dr value of the reaction crude product is 1: 5; the ee value of anti-4d is obtained by analyzing the derivative of N, N-thiocarbonyldiimidazole through HPLC, and the ee value is 70 percent; the ee value of syn-4d was 88% as determined by HPLC analysis of a derivative of N, N-thiocarbonyldiimidazole.
anti-4d:Light yellow solid；1H NMR(400MHz,CDCl3)δ7.40-7.34(m,2H), 7.33-7.22(m,6H),7.21-7.10(m,2H),4.47(dd,J＝8.8,4.4Hz,1H),3.39(s,1H), 2.91-2.75(m,1H),2.49(dd,J＝14.8,4Hz,1H),1.46(s,9H).13C NMR(100MHz, CDCl3)δ172.2,145.7,145.1,128.8,128.6,128.2,127.7,126.60,126.3,126.2(JC-F＝ 286Hz),84.0,77.2(JC-F＝29Hz),56.6,45.5,36.4,27.9.HRMS m/z Calcd.for C22H27F3NO3(M+H)+:410.1938；Found:410.1941.
syn-4d:Light yellow solid；1H NMR(400MHz,CDCl3)δ7.45-7.21(m,8H), 7.19-7.11(m,2H),4.48(dd,J＝9.0,4.8Hz,1H),3.05(s,1H),2.96(dd,J＝14.4,9.0 Hz,1H),2.68(dd,J＝14.6,4.8Hz,1H),1.46(s,9H).13C NMR(100MHz,CDCl3)δ 170.2,145.5,144.9,128.64,128.56,128.5,126.6,126.17(JC-F＝286Hz),126.21,83.1, 74.4(JC-F＝26Hz),56.0,45.3,35.5,27.9.HRMS m/z Calcd.for C22H27F3NO3(M+H)+: 410.1938；Found:410.1940.
Example 5:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4e
Figure BDA0002377367840000141
Trifluoromethyl ketone 3e (0.463g,1.0mmol), tert-butyl glycinate 2(0.195g,1.50mmol) were successively introduced,
CH3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, injection of CH2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol), stirring at room temperature for 1 hour, removing the organic solvent by spinning, and performing column chromatography to obtain the compounds anti-4e (colorless liquid) and syn-4e (colorless liquid), (total weight of the product 0.428g, total yield 72%).
Dr value of 4e is determined by1H NMR analysis is carried out on the reaction crude product, and the dr value of the reaction crude product is 1: 3; the ee value of anti-4e is obtained by analyzing the derivative of N, N-thiocarbonyldiimidazole through HPLC, and the ee value is 90 percent; the ee value of syn-4e was 97% as determined by HPLC analysis of a derivative of N, N-thiocarbonyldiimidazole.
anti-4e:colorless liquid；1H NMR(400MHz,CDCl3)δ7.73-7.62(m,4H),7.48-7.32(m,6H),3.65(dd,J＝12.0,5.6Hz,3H),1.67(dd,J＝9.6,6.6Hz,2H),1.62-1.53 (m,2H),1.50(s,9H),1.46-1.33(m,4H),1.33-1.24(m,2H),1.05(s,9H).13C NMR (100MHz,CDCl3)δ171.8,135.7,134.3,129.6,127.7,126.2(JC-F＝286Hz),83.6, 75.5(JC-F＝26Hz),64.0,56.7,32.7,32.2,30.0,28.0,27.0,25.8,22.4,19.4.HRMS m/z Calcd.forC30H45F3NO4Si(M+H)+:568.3065；Found:568.3065.
syn-4e:Colorless liquid；1H NMR(400MHz,CDCl3)δ7.75-7.60(m,4H),7.47-7.33(m,6H),3.66(t,J＝6.4Hz,2H),3.48(s,1H),1.88(t,J＝8.2Hz,2H),1.64-1.50 (m,3H),1.48(s,9H),1.45-1.20(m,5H),1.05(s,9H).13C NMR(100MHz,CDCl3)δ 170.5,135.7,134.2,129.6,127.7,126.3(JC-F＝286Hz),82.9,74.7(JC-F＝26Hz)64.0, 56.5,32.7,31.4,29.8,28.0,27.0,25.9,22.4,19.4.HRMS m/z Calcd.for C30H45F3NO4Si (M+H)+:568.3065；Found:568.3063.
Example 6:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4f
Figure BDA0002377367840000151
Trifluoromethyl ketone 3f (0.281g,1.0mmol), tert-butyl glycinate 2(0.195g,1.50mmol) were successively introduced,
CH3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, injection of CH2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol) at room temperature for 1 hour, removing the organic solvent by spinning, and performing column chromatography to obtain the compounds anti-4f (pale yellow solid) and syn-4f (pale yellow solid), (total weight of product 0.352g, total yield 85%).
Dr value of 4f is determined by1H NMR analysis is carried out on the reaction crude product, and the dr value of the reaction crude product is 1: 4; the ee value of anti-4f is obtained by analyzing the derivative of N, N-thiocarbonyldiimidazole through HPLC, and the ee value is 88%; the ee value of syn-4f was 96% by HPLC analysis of the N, N-thiocarbonyldiimidazole derivative.
anti-4f:Light yellow solid；1H NMR(400MHz,CDCl3)δ7.52(d,J＝8.0Hz,1H),7.36-7.17(m,2H),7.10-7.02(m,1H),3.70(s,1H),2.94(dd,J＝9.8,7.4Hz,2H), 2.13-1.76(m,2H),1.48(s,9H).13C NMR(100MHz,CDCl3)δ171.6,141.1,133.0, 130.5,128.0,127.8,126.1(JC-F＝285Hz),124.5,83.8,74.3(JC-F＝26Hz),56.9,32.4, 29.59,29.57,27.9.HRMS m/z Calcd.for C16H22BrF3NO3(M+H)+:412.0730；Found: 412.0733.
syn-4f:Light yellow solid；1H NMR(400MHz,CDCl3)δ7.54(dd,J＝8.0,1.2Hz,1H),7.32–7.20(m,2H),7.07(ddd,J＝7.8,6.8,2.0Hz,1H),3.56(s,1H),3.02(td,J＝12.6,4.6Hz,1H),2.89(td,J＝12.6,5.2Hz,1H),2.32-2.22(m,1H),2.21-2.11(m, 1H),1.49(s,9H).13C NMR(100MHz,CDCl3)δ170.4,141.0,132.9,130.5,127.9, 127.7,126.1(JC-F＝285Hz),124.4,83.3,74.3(JC-F＝26Hz),56.9,32.1,29.4,27.1. HRMS m/zCalcd.for C16H22BrF3NO3(M+H)+:412.0730；Found:412.0734.
Example 7:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of 4g of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester
Figure BDA0002377367840000161
3g (0.244g,1.0mmol) of trifluoromethyl ketone, tert-butyl glycinate 2(0.195g,1.50mmol), CH3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, injection of CH2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol), stirring at room temperature for 1 hour, removing the organic solvent by rotation, and column-chromatographing to give the compounds anti-4g (pale yellow solid) and syn-4g (pale yellow solid), (total weight of product 0.310g, total yield83％)。
Dr value of 4g is determined by1H NMR analysis is carried out on the reaction crude product, and the dr value of the reaction crude product is 1: 3; the ee value of anti-4g is obtained by analyzing the derivative of N, N-thiocarbonyldiimidazole through HPLC, and the ee value is 88 percent; the ee of syn-4g was determined by HPLC analysis of the N, N-thiocarbonyldiimidazole derivative and was 95%.
anti-4g:Light yellow solid；1H NMR(400MHz,CDCl3)δ6.84(s,2H),3.68(s,1H),2.90-2.75(m,2H),2.31(s,6H),2.25(s,3H),1.79(dd,J＝11.6,5.6Hz,2H),1.50 (s,9H).13C NMR(100MHz,CDCl3)δ171.9,136.3,135.4,135.2,129.1,126.1(JC-F＝ 285Hz),83.7,74.4(JC-F＝26Hz),57.1,31.5,28.0,22.2,20.9,19.6.HRMS m/z Calcd. forC19H29F3NO3(M+H)+:376.2094；Found:376.2096.
syn-4g:Light yellow solid；1H NMR(400MHz,CDCl3)δ6.85(s,2H),3.56(s, 1H),2.92-2.80(m,1H),2.79-2.50(m,1H),2.34(s,6H),2.26(s,3H),2.04(dd,J＝ 9.6,7.6Hz,2H),1.50(s,9H).13C NMR(100MHz,CDCl3)δ170.6,136.2,135.4,135.2, 129.0,126.2(JC-F＝286Hz)83.4,77.4,74.4(JC-F＝26Hz),56.8,31.1,28.1,22.2,20.9, 19.7.HRMS m/zCalcd.for C19H29F3NO3(M+H)+:376.2094；Found:376.2096.
Example 8:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4h
Figure BDA0002377367840000171
Trifluoromethyl ketone 3h (0.232g,1.0mmol), Glycine tert-butyl ester 2(0.195g,1.50mmol), CH3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, injection of CH2Cl2(4.0mL) and reacted at-10 ℃ for 48 hoursAdding hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol) at room temperature for 1 hour, removing the organic solvent by rotation, and performing column chromatography to obtain the compounds anti-4h (yellow liquid) and syn-4h (yellow liquid), (total weight of the product 0.305g, total yield 84%).
Dr value of 4h is determined by1H NMR analysis is carried out on the reaction crude product, and the dr value of the reaction crude product is 1: 4; the ee value of anti-4h is obtained by analyzing the derivative of N, N-thiocarbonyl diimidazole by HPLC, and the ee value is 83 percent; the ee value of syn-4h was 91% as determined by HPLC analysis of a derivative of N, N-thiocarbonyldiimidazole.
anti-4h:Yellow liquid；1H NMR(600MHz,CDCl3)δ7.12(d,J＝8.2Hz,2H), 6.83(d,J＝8.6Hz,2H),3.78(s,3H),3.68(s,1H),2.80-2.68(m,2H),2.10-1.90(m, 2H),1.49(s,9H).13C NMR(100MHz,CDCl3)δ171.8,158.1,133.9,129.3,126.2(JC-F＝286Hz),114.1,83.7,75.4(JC-F＝26Hz),56.7,55.4,34.5,28.0.HRMS m/z Calcd.for C17H25F3NO4(M+H)+:364.1730；Found:364.1717.
syn-4h:Yellow liquid；1H NMR(600MHz,CDCl3)δ7.15(d,J＝8.6Hz,2H), 6.84(d,J＝8.6Hz,2H),3.79(s,3H),3.56(s,1H),2.81(td,J＝12.1,11.4,5.2Hz,1H), 2.74-2.66(m,1H),2.26-2.08(m,2H),1.51(s,9H).13C NMR(100MHz,CDCl3)δ 170.3,158.1,133.6,129.4,126.2(JC-F＝286Hz),114.1,83.2,74.4(JC-F＝26Hz),56.4, 55.3,33.8,28.0.HRMSm/z Calcd.for C17H25F3NO4(M+H)+:364.1730；Found: 364.1732.
Example 9:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4i
Figure BDA0002377367840000181
Trifluoromethyl ketone 3i (0.208g,1.0mmol), tert-butyl glycinate 2 (g, g0.195g,1.50mmol),CH3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, injection of CH2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol), stirring at room temperature for 1 hour, removing the organic solvent by rotation, and column-chromatographing to give the compounds anti-4i (colorless liquid) and syn-4i (colorless liquid), (total weight of product 0.261g, total yield 77%).
Dr value of 4i is determined by1H NMR analysis shows that the reaction crude product is obtained, and the dr value of the reaction crude product is 1: 5; the ee value of anti-4i is obtained by analyzing the derivative of N, N-thiocarbonyldiimidazole through HPLC, and the ee value is 84%; the ee value of syn-4i was 95% as determined by HPLC analysis of a derivative of N, N-thiocarbonyldiimidazole.
anti-4i:Colorless liquid；1H NMR(600MHz,CDCl3)δ3.61(s,1H),1.78-1.57(m,7H),1.49(s,9H),1.42-1.27(m,2H),1.26-1.07(m,4H),0.98-0.78(m,2H).13C NMR(100MHz,CDCl3)δ171.8,126.2(JC-F＝286Hz),83.6,75.7(JC-F＝26Hz),56.7, 38.3,33.4,33.3,29.71,29.65,28.0,26.8,26.45,26.43.HRMS m/z Calcd.for C16H29F3NO3(M+H)+:340.2094；Found:340.2092.
syn-4i:Colorless liquid；1H NMR(600MHz,CDCl3)δ3.47(s,1H),1.98-1.80(m,2H),1.79-1.59(m,5H),1.47(s,9H),1.46–1.40(m,1H),1.32-1.09(m,5H),1.00- 0.80(m,2H).13C NMR(100MHz,CDCl3)δ170.6,126.2(JC-F＝286Hz),83.0, 74.7(JC-F＝26Hz),56.3,38.3,33.7,33.3,29.7,28.8,28.0,26.7,26.44,26.42.HRMS m/z Calcd.for C16H29F3NO3(M+H)+:340.2094；Found:340.2092.
Example 10:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4j
Figure BDA0002377367840000191
Trifluoromethyl ketone 3j (0.222g,1.0mmol), tert-butyl glycinate 2(0.195g,1.50mmol), CH3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, injection of CH2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol), stirring at room temperature for 1 hour, removing the organic solvent by rotation, and column-chromatographing to give the compounds anti-4j (colorless liquid) and syn-4j (colorless liquid), (total weight of product 0.247g, total yield 70%).
Dr value of 4j is determined by1H NMR analysis shows that the reaction crude product is obtained, and the dr value of the reaction crude product is 1: 3.5; the ee value of anti-4j is obtained by analyzing the derivative of N, N-thiocarbonyldiimidazole through HPLC, and the ee value is 85 percent; the ee value of syn-4j was determined by HPLC analysis of the N, N-thiocarbonyldiimidazole derivative and was 96%.
anti-4j:Colorless liquid；1H NMR(400MHz,CDCl3)δ5.90-5.70(m,1H),5.08-4.82(m,2H),3.63(s,1H),2.11-1.98(m,2H),1.74-1.61(m,2H),1.50(s,9H),1.40- 1.20(m,10H).13C NMR(100MHz,CDCl3)δ171.8,139.3,126.2(JC-F＝288Hz),114.3, 83.6,75.6(JC-F＝26Hz),56.7,33.9,32.3,30.2,29.4,29.2,29.0,28.0,22.4.HRMS m/z Calcd.forC17H31F3NO3(M+H)+:354.2251；Found:354.2249.
syn-4j:Colorless liquid；1H NMR(400MHz,CDCl3)δ5.90-5.70(m,1H),5.04-4.86(m,2H),3.48(s,1H),2.09-1.98(m,2H),1.88(t,J＝8.2Hz,2H),1.48(s,9H), 1.42-1.22(m,10H).13C NMR(100MHz,CDCl3)δ170.5,139.2,126.3(JC-F＝288Hz), 114.2,82.3,74.7(JC-F＝26Hz),56.5,33.9,31.4,30.0,29.5,29.1,29.0,27.9,22.3. HRMS m/zCalcd.for C17H31F3NO3(M+H)+:354.2251；Found:354.2248.
Example 11:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4k
Figure BDA0002377367840000201
Trifluoromethyl ketone 3k (0.274g,1.0mmol), tert-butyl glycinate 2(0.195g,1.50mmol), CH were successively reacted3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, injection of CH2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol), stirring at room temperature for 1 hour, removing the organic solvent by spinning, and performing column chromatography to obtain the compounds anti-4k (colorless liquid) and syn-4k (colorless liquid), (total weight of the product 0.309g, total yield 76%).
Dr value of 4k is determined by1H NMR analysis is carried out on the reaction crude product, and the dr value of the reaction crude product is 1: 3; the ee value of anti-4k is obtained by analyzing the derivative of N, N-thiocarbonyldiimidazole through HPLC, and the ee value is 88%; the ee value of syn-4k was determined by HPLC analysis of the N, N-thiocarbonyldiimidazole derivative and was 96%.
anti-4k:Colorless liquid；1H NMR(400MHz,CDCl3)δ7.34(d,J＝5.0Hz,4H),7.33-7.22(m,1H),4.50(s,2H),3.62(s,1H),3.46(t,J＝6.6Hz,2H),1.71-1.57(m, 4H),1.49(s,9H),1.47-1.22(m,4H).13C NMR(100MHz,CDCl3)δ171.8,138.8, 128.4,127.7,127.6,126.2(JC-F＝286Hz),83.6,75.6(JC-F＝26Hz),73.0,70.5,56.6, 32.2,30.0,29.8,28.0,26.2,22.4.HRMS m/z Calcd.for C21H33F3NO4(M+H)+: 420.2356；Found:420.2351.
syn-4k:Colorless liquid；1H NMR(400MHz,CDCl3)δ7.34(d,J＝4.0Hz,4H),7.31-7.24(m,1H),4.50(s,2H),3.53–3.37(m,3H),1.89(t,J＝8.0Hz,2H),1.68- 1.58(m,2H),1.47(s,9H),1.45-1.28(m,4H).13C NMR(100MHz,CDCl3)δ170.4, 138.8,128.4,127.7,127.5,126.2(JC-F＝286Hz),82.9,74.6(JC-F＝26Hz),72.9,70.4, 56.4,31.3,29.81,29.77,27.9,26.2,22.3.HRMS m/z Calcd.for C21H33F3NO4(M+H)+: 420.2356；Found:420.2351.
Example 12:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4l
Figure BDA0002377367840000211
3l (0.216g,1.0mmol) of trifluoromethyl ketone, tert-butyl glycinate 2(0.195g,1.50mmol), CH3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, injection of CH2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol), stirring at room temperature for 1 hour, removing the organic solvent by spinning, and column-chromatographing to give the compounds anti-4l (colorless liquid) and syn-4l (colorless liquid), (total weight of product 0.347g, total yield 80%).
Dr value of 4l is determined by1H NMR analysis is carried out on the reaction crude product, and the dr value of the reaction crude product is 1: 6; the ee value of anti-4l is obtained by analyzing the derivative of N, N-thiocarbonyldiimidazole through HPLC, and the ee value is 86 percent; the ee value of syn-4l was 95% as determined by HPLC analysis of a derivative of N, N-thiocarbonyldiimidazole.
anti-4l:Colorless liquid；1H NMR(600MHz,CDCl3)δ7.33-7.24(m,2H),7.23-7.09(m,3H),3.60(s,1H),2.70–2.51(m,2H),1.94-1.66(m,4H),1.45(s,9H).13C NMR(150MHz,CDCl3)δ171.7,141.9,128.49,128.46,126.1(JC-F＝286Hz),126.0, 83.6,75.5(JC-F＝26Hz),56.6,36.3,31.9,27.9,24.2.HRMS m/z Calcd.for C17H25F3NO3(M+H)+:348.1781；Found:348.1780.
syn-4l:Colorless liquid；1H NMR(600MHz,CDCl3)δ7.31-7.23(m,2H),7.21-7.15(m,3H),3.43(s,1H),2.75-2.66(m,1H),2.65-2.58(m,1H),2.03-1.84(m,3H), 1.83-1.70(m,1H),1.42(s,9H).13C NMR(150MHz,CDCl3)δ170.4,142.0,128.5, 126.2(JC-F＝286Hz),83.0,74.6(JC-F＝26Hz),56.6,36.3,31.3,27.9,24.5.HRMS m/z Calcd.forC17H25F3NO3(M+H)+:348.1781；Found:348.1780.
Example 13:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4m
Figure BDA0002377367840000221
Trifluoromethyl ketone 3m (0.334g,1.0mmol), glycine tert-butyl ester 2(0.195g,1.50mmol), CH3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, injection of CH2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol), stirring at room temperature for 1 hour, removing the organic solvent by spinning, and performing column chromatography to obtain the compounds anti-4m (colorless liquid) and syn-4m (colorless liquid), (total weight of the product 0.382g, total yield 82%).
Dr value of 4m is determined by1H NMR analysis shows that the reaction crude product is obtained, and the dr value of the reaction crude product is 1: 5; the ee value of anti-4m is obtained by analyzing the derivative of N, N-thiocarbonyl diimidazole by HPLC, and the ee value is 90 percent; the ee value of syn-4m was 93% by analyzing the N, N-thiocarbonyldiimidazole derivative by HPLC.
anti-4m:Colorless liquid；1H NMR(400MHz,CDCl3)δ5.43-5.17(m,2H),3.62 (s,1H),2.00(q,J＝6.4,6.0Hz,4H),1.76-1.59(m,2H),1.49(s,9H),1.28(d,J＝12.4 Hz,22H),0.87(t,J＝6.6Hz,3H).13C NMR(100MHz,CDCl3)δ171.8,130.1,129.9, 126.2(JC-F＝286Hz),83.6,75.6(JC-F＝26Hz),56.6,32.3,32.0,30.2,29.92,29.88,29.7, 29.53,29.47,29.4,28.0,27.4,27.3,22.8,22.4,14.2.HRMS m/z Calcd.for C25H47F3NO3(M+H)+:466.3503；Found:466.3498.
syn-4m:Colorless liquid；1H NMR(400MHz,CDCl3)δ5.39-5.28(m,2H),3.47 (s,1H),2.10-1.95(m,4H),1.87(t,J＝8.2Hz,2H),1.47(s,9H),1.39-1.19(m,22H), 0.87(t,J＝6.6Hz,3H).13C NMR(100MHz,CDCl3)δ170.5,130.1,129.9,126.3(JC-F＝ 286Hz),83.0,74.7(JC-F＝26Hz),56.5,32.0,31.4,30.0,29.91,29.87,29.7,29.6,29.46, 29.45,29.4,28.0,27.4,27.3,22.8,22.4,14.2.HRMS m/z Calcd.for C25H47F3NO3(M+H)+:466.3503；Found:466.3497.
Example 14:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4n
Figure BDA0002377367840000231
Trifluoromethyl ketone 3n (0.222g,1.0mmol), tert-butyl glycinate 2(0.195g,1.50mmol), CH3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, injection of CH2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol), stirring at room temperature for 1 hour, removing the organic solvent by spinning, and column-chromatographing to give the compounds anti-4n (colorless liquid) and syn-4n (colorless liquid), (total weight of product 0.285g, total yield 80%).
Dr value of 4n is determined by1H NMR analysis of the crude reaction product to obtainTo, its dr value is 1: 4; the ee value of anti-4N is obtained by analyzing the derivative of N, N-thiocarbonyldiimidazole through HPLC, and the ee value is 97 percent; the ee value of syn-4N was 95% by HPLC analysis of a derivative of N, N-thiocarbonyldiimidazole.
anti-4n:Colorless liquid；1H NMR(600MHz,CDCl3)δ5.12-5.03(m,1H),3.61 (s,1H),2.07-1.88(m,2H),1.87-1.78(m,1H),1.71(dd,J＝14.8,4.4Hz,1H),1.67(d, J＝1.4Hz,3H),1.59(s,3H),1.49(s,9H),1.46-1.37(m,2H),1.30-1.10(m,1H),1.00 (d,J＝6.6Hz,3H).13C NMR(150MHz,CDCl3)δ171.7,131.4,126.2(JC-F＝286Hz), 124.8,83.5,76.2(JC-F＝26Hz),57.3,38.7,38.3,28.1,28.0,25.8,25.6,21.7,17.7. HRMS m/z Calcd.forC17H31F3NO3(M+H)+:354.2251；Found:354.2249.
syn-4n:Colorless liquid；1H NMR(600MHz,CDCl3)δ5.12-5.03(m,1H),3.50 (s,1H),2.10-1.92(m,2H),1.89(dd,J＝14.0,2.6Hz,1H),1.81-1.70(m,2H),1.67(s, 3H),1.59(s,3H),1.47(s,9H),1.45-1.40(m,1H),1.30-1.18(m,1H),1.03(d,J＝6.4 Hz,3H).13CNMR(150MHz,CDCl3)δ170.5,131.5,126.2(JC-F＝286Hz),124.7,83.2, 76.2(JC-F＝26Hz),56.6-3,39.0,37.6,28.2,28.0,25.8,25.4,20.7,17.8.HRMS m/z Calcd.for C17H31F3NO3(M+H)+:354.2251；Found:354.2249.
Example 15:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4o
Figure BDA0002377367840000241
Trifluoromethyl ketone 3o (0.342g,1.0mmol), tert-butyl glycinate 2(0.195g,1.50mmol), CH were successively reacted3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, injection of CH2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol), stirring at room temperature for 1 hour, removing the organic solvent by rotation, and column-chromatographing to give the compounds anti-4o (pale yellow solid) and syn-4o (pale yellow solid), (total weight of product 0.300g, total yield 63%).
Dr value of 4o is determined by1H NMR analysis shows that the reaction crude product is obtained, and the dr value of the reaction crude product is 1: 5; the ee value of anti-4o is obtained by analyzing the derivative of N, N-thiocarbonyldiimidazole through HPLC, and the ee value is 85 percent; the ee value of syn-4o was 97% as determined by HPLC analysis of a derivative of N, N-thiocarbonyldiimidazole.
anti-4o:Light yellow solid；1H NMR(600MHz,CDCl3)δ8.28(d,J＝9.2Hz,1H),8.20-8.13(m,2H),8.11(dd,J＝8.4,2.8Hz,2H),8.05-7.97(m,3H),7.88(d,J＝7.6 Hz,1H),3.61(s,1H),3.43-3.33(m,2H),2.18-2.00(m,2H),1.95(dd,J＝9.0,7.2Hz, 2H),1.43(s,9H).13C NMR(150MHz,CDCl3)δ171.7,136.2,131.5,131.03,130.00, 128.8,127.6,127.4,127.2,126.7,126.2(JC-F＝286Hz),125.9,125.2,125.1,125.0, 124.9,124.8,123.4,75.6(JC-F＝26Hz),83.7,56.6,33.9,32.2,27.9,24.6.HRMS m/z Calcd.forC27H29F3NO3(M+H)+:472.2083；Found:472.2088.
syn-4o:Light yellow solid；1H NMR(600MHz,CDCl3)δ8.28(d,J＝9.1Hz,1H),8.20-8.15(m,2H),8.11(t,J＝8.6Hz,2H),8.06-7.96(m,3H),7.88(d,J＝7.6Hz, 1H),3.49-3.40(m,2H),3.39-3.30(m,1H),2.31-2.07(m,3H),2.07-1.94(m,1H), 1.36(s,9H).13C NMR(150MHz,CDCl3)δ170.3,136.4,131.5,131.0,130.0,128.7, 127.6,127.44,127.35,126.8,126.2(JC-F＝286Hz),126.0,125.3,125.1,125.03,124.98, 124.8,123.4,74.6(JC-F＝26Hz),83.1,56.4,33.9,31.5,27.8,24.9.HRMS m/z Calcd.for C27H29F3NO3(M+H)+:472.2094；Found:472.2088.
Example 16:
chiral pyridoxal catalyst (S) -1 catalyzed synthesis of chiral β -trifluoromethyl- β -hydroxy- α -amino acid ester 4p
Figure BDA0002377367840000251
Trifluoromethyl ketone 3p (0.202g,1.0mmol), tert-butyl glycinate 2(0.195g,1.50mmol), CH3COOH (0.030g,0.50mmol) and chiral pyridoxal catalyst (S) -1(0.0005g,0.001mmol) were placed in a 5mL reaction flask, and a stirrer was added, followed by covering with a rubber stopper and replacing N2Three times, injection of CH2Cl2(4.0mL), reaction at-10 ℃ for 48 hours, and addition of hydroxylamine hydrochloride (HONH)2HCl,0.070g,1.0mmol) and sodium bicarbonate (NaHCO)30.084g,1.0mmol), stirring at room temperature for 1 hour, removing the organic solvent by rotation, and column-chromatographing to give the compounds anti-4p (colorless liquid) and syn-4p (colorless liquid), (total weight of product 0.292g, total yield 88%).
Dr value of 4p is determined by1H NMR analysis is carried out on the reaction crude product, and the dr value of the reaction crude product is 1: 6; the ee value of anti-4p is obtained by analyzing the derivative of N, N-thiocarbonyldiimidazole through HPLC, and the ee value is 85 percent; the ee value of syn-4p was 96% by HPLC analysis of the N, N-thiocarbonyldiimidazole derivative.
anti-4p:Colorless liquid；1H NMR(400MHz,CDCl3)δ7.32-7.25(m,2H),7.23-7.15(m,3H),3.68(s,1H),2.85-2.75(m,2H),2.07-1.86(m,2H),1.49(d,J＝1.2Hz, 9H).13CNMR(100MHz,CDCl3)δ171.8,141.8,128.6,128.5,126.2(JC-F＝286Hz), 83.8,75.4(JC-F＝26Hz),56.7,34.3,28.9,28.0.HRMS m/z Calcd.for C16H23F3NO3(M+H)+:334.1625；Found:334.1624.
syn-4p:Colorless liquid；1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.25-7.16(m,3H),3.56(s,1H),2.95-2.68(m,2H),2.30–2.10(m,2H),1.50(s,9H).13C NMR(100MHz,CDCl3)δ170.3,141.6,128.62,128.56,126.18(JC-F＝286Hz),126.17, 83.3,74.5(JC-F＝26Hz),56.5,33.6,28.9,28.0.HRMS m/z Calcd.for C16H23F3NO3(M+H)+:334.1625；Found:334.1623.
The preparation processes of various chiral β -trifluoromethyl- β -hydroxy- α -amino acids and derivatives thereof in the above examples are mainly prepared by referring to the following procedures:
Figure BDA0002377367840000261
in the preparation process, R4、R5May be hydrogen, substituted or unsubstituted: c1～C24A hydrocarbon group of3～C30Cycloalkyl or aryl of, C1～C24Carbonyl group of (C)1～C24Sulfonyl or phosphoryl groups of (a); wherein said substitution is with the following substituents: halogen, C1～C8A hydrocarbon group of3～C12Cycloalkyl or aryl of, C1～C8Carbonyl group of (C)1～C8Sulfonyl or phosphoryl, C1～C8The carbonyl group refers to an aldehyde group, a ketocarbonyl group, an ester carbonyl group, a carboxyl group or an amide group.
Meanwhile, the solvent used in the preparation process can be replaced by water, benzene, toluene, xylene, trimethylbenzene, acetonitrile, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, carbon tetrachloride, chloroform, dichloromethane, 1, 2-dichloroethane, methanol, ethanol, isopropanol, tert-butanol, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and the like; the acid used may be replaced with sulfuric acid, hydrochloric acid, a dichloromethane solution of hydrochloric acid, a methanol solution of hydrochloric acid, a tetrahydrofuran solution of hydrochloric acid, a dioxane solution of hydrochloric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid or the like.
In addition, the addition amount of each raw material can be arbitrarily adjusted within the following range (i.e., the middle point or the end point thereof is arbitrarily selected) as required: the molar ratio of glycine and the derivative 2 thereof to trifluoromethyl ketone 3 is 0.5: 1-5: 1;
the molar ratio of pyridoxal catalyst 1 to trifluoromethyl ketone 3 was 0.001: 1-0.5: 1;
the reaction temperature is-40 to 100 ℃, and the reaction time is 1 to 144 hours.
Finally, other starting materials or processing techniques not specifically described are all conventional commercial starting materials or conventional processing techniques in the art.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make modifications and alterations without departing from the scope of the present invention.

Claims (10)

1. A method for preparing chiral β -trifluoromethyl- β -hydroxy- α -amino acid and derivatives thereof is characterized in that tert-butyl glycinate and derivatives thereof, trifluoromethyl ketone, acid and chiral N-methyl pyridoxal catalyst are weighed, added with solvent and reacted to generate target products of chiral β -trifluoromethyl- β -hydroxy- α -amino acid and derivatives thereof;
the structural formulas of the tert-butyl glycinate or derivatives thereof, the trifluoromethyl ketone, the chiral N-methyl pyridoxal catalyst, the chiral β -trifluoromethyl- β -hydroxy- α -amino acid or derivatives thereof are respectively as follows:
Figure FDA0002377367830000011
wherein R is1Is hydrogen or C1-C24A hydrocarbon group of R2And R3Each independently is hydrogen or C1-C24A hydrocarbon group of (a);
R4、R5each independently is hydrogen, or any of the following substituted or unsubstituted groupsOne of them is: c1～C24A hydrocarbon group of3～C30Cycloalkyl or aryl of, C1～C24Carbonyl group of (C)1～C24Sulfonyl or phosphoryl groups.
2. The method of claim 1, wherein R is selected from the group consisting of chiral β -trifluoromethyl- β -hydroxy- α -amino acids and derivatives thereof5When substituted, it is meant substituted with any of the following substituents: halogen, C1～C8A hydrocarbon group of3～C12Cycloalkyl or aryl of, C1～C8Carbonyl group of (C)1～C8Sulfonyl or phosphoryl, C1～C8Alkoxy or amine groups of (a).
3. A process according to claim 1 for the preparation of chiral β -trifluoromethyl- β -hydroxy- α -amino acid and derivatives thereof, wherein the acid used is sulfuric acid, hydrochloric acid, dichloromethane solution of hydrochloric acid, methanol solution of hydrochloric acid, tetrahydrofuran solution of hydrochloric acid, dioxane solution of hydrochloric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid;
the solvent used is one or more of the following solvents:
water, benzene, toluene, xylene, trimethylbenzene, acetonitrile, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, carbon tetrachloride, chloroform, dichloromethane, 1, 2-dichloroethane, methanol, ethanol, isopropanol, N-propanol, N-butanol, tert-butanol, trifluoroethanol, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.
4. The method for preparing the chiral β -trifluoromethyl- β -hydroxy- α -amino acid and its derivatives as claimed in claim 1, wherein the molar ratio of tert-butyl glycinate or its derivatives to trifluoromethyl ketone is 0.5:1 to 5: 1;
the molar ratio of chiral N-methyl pyridoxal catalyst to trifluoromethyl ketone was 0.0001: 1-0.5: 1;
the reaction temperature is-40 to 100 ℃, and the reaction time is 1 to 144 hours.
5. The method of claim 1, wherein R is selected from the group consisting of chiral β -trifluoromethyl- β -hydroxy- α -amino acids and derivatives thereof1Selected C1-C24The hydrocarbon group is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, (1-phenyl) ethyl, 1-naphthyl, 2-naphthyl or halogen.
6. The method of claim 1, wherein R is selected from the group consisting of chiral β -trifluoromethyl- β -hydroxy- α -amino acids and derivatives thereof2Or R3Selected C1-C24The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2, 6-biphenyl, 3, 5-biphenyl, 1-naphthyl or 2-naphthyl.
7. The process for the preparation of chiral β -trifluoromethyl- β -hydroxy- α -amino acid and its derivatives as claimed in claim 1, wherein the chiral N-methyl pyridoxal catalyst is prepared by:
(1) placing carboxylic acid compounds 5', (S) -BINOL, a condensing agent and alkali in a solvent for reaction to obtain a compound 6 with two configurations;
(2) taking a compound 6 with a single configuration, removing BINOL under the action of alkali, and then acidifying to obtain a chiral acid compound 5 with a single configuration;
(3) condensing a chiral acid compound 5 with a single configuration with a chiral amino alcohol compound 7 to generate a compound 8;
(4) firstly, obtaining a methylated intermediate from the compound 8 under the action of methyl iodide, and hydrolyzing the methylated intermediate under the action of acid to obtain a target product pyridoxal catalyst;
the structural general formulas of the carboxylic acid compound 5', the compound 6 with two configurations, the chiral acid compound 5 with two configurations, the chiral amino alcohol compound 7 and the compound 8 are respectively as follows:
Figure FDA0002377367830000031
8. the method for preparing chiral β -trifluoromethyl- β -hydroxy- α -amino acid and its derivatives as claimed in claim 7, wherein the molar ratio of the carboxylic acid compound 5' to the condensing agent in step (1) is 1 (1-5);
in the step (2), the molar ratio of the compound 6 to the base is 1: (1-10);
in the step (3), the molar ratio of the chiral acid compound 5 to the chiral amino alcohol compound 7 is 1: (1-5);
in the step (4), the molar ratio of the compound 8 to the methyl iodide is 1: (1-50).
9. The method for preparing the chiral β -trifluoromethyl- β -hydroxy- α -amino acid and its derivatives as claimed in claim 7, wherein the reaction temperature in step (1) is-20 to 50 ℃ and the reaction time is 1 to 48 hours;
in the step (2), the reaction temperature is-20-120 ℃, and the reaction time is 1-72 h;
in the step (3), the reaction temperature is 0-100 ℃, and the reaction time is 1-24 h;
in the step (4), the reaction temperature is 0-100 ℃, and the reaction time is 1-48 h.
10. A process according to claim 7 for the preparation of chiral β -trifluoromethyl- β -hydroxy- α -amino acid and its derivatives wherein the base used is a combination of one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, calcium hydride, potassium fluoride, triethylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, N-dimethylaniline, N-diethylaniline, 1, 4-diazabicyclooctane, diazabicyclododecane, N-butyllithium, 1, 4-dimethylpiperazine, 1-methylpiperidine, 1-methylpyrrole, quinoline or pyridine;
the acid used is one or more of sulfuric acid, hydrochloric acid, dichloromethane solution of hydrochloric acid, methanol solution of hydrochloric acid, tetrahydrofuran solution of hydrochloric acid, dioxane solution of hydrochloric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid;
the solvent is water, benzene, toluene, xylene, trimethylbenzene, acetonitrile, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, chloroform, dichloromethane, methanol, ethanol, isopropanol, tert-butanol, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide or N-methylpyrrolidone.
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